A recurring theme in pulmonary fibrosis genetics.

In 1980, the question “Is there a fibrotic gene?” was posed in an editorial [1] commenting on a report about pulmonary fibrosis in monozygotic twins. Over the next 37 years, the identification of kindreds of families with pulmonary fibrosis and advances in DNA sequencing provided answers to this question. An early example of a gene associated with pulmonary fibrosis involved a case of familial pulmonary fibrosis (FPF) that was linked to a heterozygous mutation in the surfactant protein C (SFTPC) gene, which is expressed predominantly by alveolar type-II (ATII) cells in the lung [2]. This was followed by reports that mutations in other ATII cell associated genes (ABCA3 and SFTPA) had been identified in patients with FPF. Similarly, candidate gene and whole-genome linkage scanning approaches identified mutations in TERT and TERC, two genes required for telomere maintenance, in kindreds of pulmonary fibrosis patients. These findings were followed by the association of other genes involved in telomere maintenance (DKC1, RTEL1, PARN, TIN2, and NAF1) to FPF. Overall, mutations in these ten ATII cell and telomere associated genes are predicted to account for up to 25% of genes associated with FPF [3, 4], which can present as different clinical syndromes including idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis, pleuroparenchymal fibroelastosis, interstitial pneumonia with autoimmune features, or idiopathic nonspecific interstitial pneumonia [5, 6].